NOC/oFQ PKC-dependent superoxide generation contributes to hypoxic-ischemic
impairment of NMDA cerebrovasodilation.
Armstead, William M.
Departments of Anesthesia and Pharmacology, University of Pennsylvania, Philadelphia,
Pennsylvania 19104
APStracts 7:0470H, 2000.
This study determined whether nociceptin/orphanin FQ (NOC/oFQ) generates superoxide anion
(«o2») in a protein kinase C (PKC)-dependent manner and whether such production contributes
to hypoxic-ischemic (H-I) impairment of N-methyl-d-aspartate (NMDA)-induced pial artery
dilation in newborn pigs equipped with closed cranial windows. Superoxide dismutase (SOD)-
inhibitable nitroblue tetrazolium (NBT) reduction was an index of «o2» generation. Under non-
H-I conditions, topical NOC/oFQ (10«minus»10 M, concentration present in CSF after I or H-I)
increased SOD-inhibitable NBT reduction from 1 ± 1 to 20 ± 3 pmol/mm2. PKC inhibitors
staurosporine and chelerythrine (10«minus»7 M) blunted NBT reduction (1 ± 1 to 7 ± 2
pmol/mm2 for chelerythrine), whereas the NOC/oFQ receptor antagonist [F/G]NOC/oFQ (1-13)-
NH2 (10«minus»6 M) blocked NBT reduction. [F/G]NOC/oFQ(1-13)-NH2 and staurosporine
also blunted the NBT reduction observed after I or H-I. NMDA (10«minus»8, 10«minus»6 M)-
induced pial artery dilation was reversed to vasoconstriction after H-I. The NOC/oFQ antagonist
staurosporine and free radical scavengers partially prevented this impaired dilation (sham: 9 ± 1
and 16 ± 1; H-I: «minus»5 and «minus»10 ± 1; H-I staurosporine pretreated: 3 ± 1 and 6 ± 1%).
These data show that NOC/oFQ increased «o2» production in a PKC-dependent manner and
contributed to this production after insult and that NOC/oFQ contributed to impaired NMDA-
induced pial artery dilation after H-I, suggesting, therefore, that PKC-dependent «o2» generation
by NOC/oFQ links NOC/oFQ release to impaired NMDA dilation after H-I.
Received 27 April 2000; accepted in final form 25 July 2000
APS Manuscript Number H381-0.
Article publication pending Am J Physiol Heart Circ Physiol
ISSN 1080-4757 Copyright 2000 The American Physiological Society.
Published in APStracts on 20 October 2000